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Aims: Heart rate reduction therapy using ivabradine, a selective inhibitor of the funny current of the sinoatrial node, is widely used in the systolic heart failure cohort. However, the optimal target of heart rate remains controversial. The association between heart rate and 'overlap' between E-wave and A-wave in the pulse wave transmitral flow Doppler echocardiography might be a key to find the ideal heart rate in each individual., Methods and Results: We performed transthoracic echocardiography in patients with systolic heart failure, and the association between heart rate, deceleration time, and overlap length between E-wave and A-wave was assessed. In total, 368 patients with systolic heart failure (median 76 years old, 190 men, median ejection fraction 40%) were included. The measured overlap length was 35 (-72, 115) ms. Given the results of multiple linear regression analyses, we constructed a formula: estimated overlap length (ms) = -589 + 6.2 × heart rate (bpm) + 0.81 × deceleration time (ms), which had a good agreement with actually measured one (r = 0.62). The ideal heart rate, at which the overlap length is 'zero' and probably cardiac output is maximized, is calculated as follows: ideal heart rate (bpm) = 93 - 0.13 × deceleration time (ms)., Conclusions: We proposed a novel formula using deceleration time to estimate ideal heart rate that achieves a zero overlap between E-wave and A-wave in patients with systolic heart failure. Prognostic impact of the formula-guided heart rate optimization should be studied., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Patients with type 2 diabetes mellitus (T2DM) are at increased risk for impairment in heart failure and diastolic relaxation while preserving ejection fraction (EF). Recently, several sodium glucose cotransporter-2 (SGLT2) inhibitors have demonstrated to decrease cardiovascular disease (CVD) events in elderly diabetic patients, although gender difference in the effect of SGLT2 inhibitors is unknown. The objective of the present study was to evaluate gender difference in the effect of tofogliflozin, one of the SGLT2 inhibitors, on CVD function in patients with diabetes mellitus., Methods: This was a retrospective study. Patients received 20 mg of tofogliflozin daily for 3 months. EF, ratio of early filling to atrial filling (E/A), a change in mitral inflow E and mitral e' annular velocities (E/e'), left atrial dimension (LAD) and maximal diameter of inferior vena cava (IVC max ), including various physiological parameters were measured between baseline, 1 month and 3 months after administration of tofogliflozin. Interaction between gender and time after administration was evaluated using mixed effect model., Results: The results showed significant decrease in E/e' (P < 0.01) and significant interaction between time and gender in E/A (P < 0.01), following administration of tofogliflozin for 3 months. EF was constantly higher significantly in women (P < 0.01)., Conclusion: It is concluded that 3-month administration of tofogliflozin decreased E/e' with gender difference in EF and E/A., Competing Interests: None to declare., (Copyright 2020, Higashikawa et al.)

Aims: Small dense low-density lipoprotein cholesterol (sdLDL-C) and remnant-like particle cholesterol (RLP-C) are the novel atherosclerotic risk factors and might be strongly associated with inflammation. The basic evidence supports that sdLDL and RLP have some different mechanisms inducing an inflammatory response. Many studies have focused on the mechanism of inflammation of sdLDL-C or RLP-C per se, with limited data on the association between sdLDL-C and RLP-C in the real-world, population-based setting. Thus, the aim of this study was to investigate the association between sdLDL-C and RLP-C with inflammation., Methods: We examined the baseline cross-sectional data of participants from the Jichi Medical School-II Cohort Study. In total, 5,305 participants (2,439 men and 2,866 women) were included in this study., Results: Of all quartiles of sdLDL-C, the fourth had the highest high-sensitivity C-reactive protein (hs-CRP) level. Once adjusted for age, sex, smoking status, homeostasis model assessment of insulin resistance, antidyslipidemic and antihyperglycemic medication use, and RLP-C, sdLDL-C was significantly and positively associated with hs-CRP (geometric mean, 95% confidence interval (CI), 0.36 mg/L (0.34-0.38 mg/L), 0.37 mg/L (0.35-0.39 mg/L), 0.40 mg/L (0.37-0.42 mg/L) versus 0.44 mg/L (0.42-0.47 mg/L), P＜0.001 for trend). After stratifying the participants into four sdLDL-C×four RLP-C categories, the group in the fourth sdLDL-C quartile and the forth RLP-C quartile had the highest hs-CRP level (geometric mean, 95% CI, 0.52 mg/L, 0.48-0.57 mg/L, interaction P=0.75)., Conclusions: SdLDL-C and RLP-C had different associations with inflammation. Our results support sdLDL-C as the potential novel factor of cardiovascular disease, independently of RLP-C.

Hyperprogressive disease (HPD) is a paradoxical phenomenon involving the acceleration of tumor progression after treatment with immune checkpoint inhibitors (ICIs). A 66-year-old male smoker with advanced lung adenocarcinoma started pembrolizumab for progressive disease following first-line chemotherapy. He developed HPD after two cycles, and a re-biopsy revealed transformation to small-cell carcinoma. He subsequently underwent two lines of chemotherapy for small-cell carcinoma until progression and ultimately died. Transformation to small-cell carcinoma may be a cause of HPD during ICI therapy. The possibility of pathological transformation should be considered in cases of HPD with resistance to ICI therapy.

This study aimed to investigate the associations of body mass index (BMI) and metabolically unhealthy weight with all-cause mortality, cardiovascular disease (CVD) mortality, and cancer mortality as well as the effect of age on the associations. This prospective study enrolled Japanese individuals in the general population. Participants were divided into eight phenotypes according to the BMI classification and metabolic status. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a Cox regression hazard model. In total, 10,824 individuals with a mean age of 55.3 years were evaluated. During a mean follow-up of 18.4 years (198,776 person-years), 2,274 participants died. Among the metabolically unhealthy, the association between BMI and mortality was J-shaped after adjustment for various confounders (multivariable HR [95% CI] for all-cause mortality: underweight, 2.0 [1.5-2.7]; obesity 2.8 [2.1-3.6]). The association remained the same in metabolically unhealthy participants aged <65 years and ≥65 years. The results were compatible in the analyses restricted to subjects who never smoked. Regardless of age, metabolically unhealthy underweight (MUHU) have approximately a 3-fold higher risk of CVD mortality, compared with metabolically healthy normal weight. Not only metabolically unhealthy obesity, but also MUHU was strongly associated with an increased risk of mortality. More attention should be given to the health issues of metabolically unhealthy participants without obesity, particularly those with MUHU., Competing Interests: The authors have declared that no competing interests exist.

Competing Interests: Competing interests: None declared.

Competing Interests: Conflicts of Interest: None declared.

An outbreak of dengue fever occurred in Japan in August 2014. We herein report the case of a 63-year-old man who presented with a persistent fever in September 2014. Acute parvovirus B19 infection led to a false positive finding of dengue fever on a rapid diagnostic test (Panbio Dengue Duo Cassette(TM)). To the best of our knowledge, there are no previous reports of a false positive result for dengue IgM with the dengue rapid diagnostic test. We believe that epidemiological information on the prevalence of parvovirus B19 is useful for guiding the interpretation of a positive result with the dengue rapid diagnostic test.

To explore the effects of various antihypertensive regimes on microalbuminuria, an angiotensin II receptor blocker (ARB), valsartan, was substituted for or added to treatment with a calcium channel blocker (CCB). After a 6-month CCB baseline period, 28 Japanese hypertensive patients with incipient diabetic nephropathy (defined as a urinary albumin excretion [UAE] of 30-300 mg/g creatinine), were assigned to two groups according to their blood pressure (BP) levels: in patients with a BP of more than 130/85 mmHg (n=17), valsartan was added to the CCB (Group A), while in patients with a BP <130/85 mmHg, valsartan alone was given (Group B: n=11) for 12 months. UAE was determined before and at 3, 6 and 12 months after the initiation of ARB. Although the initial BP was significantly higher in Group A (150/83 mmHg) than Group B (127/77 mmHg), BP was decreased to 141/78 mmHg in Group A and slightly, but not significantly, increased to 130/82 mmHg in Group B. In both groups, UAE was significantly decreased after ARB treatment (to 89% of the basal value in Group A and to 40.5% of the basal value in Group B) and did not differ each other and the amount of decrease did not differ significantly between the two groups. These results suggest that combination therapy with an ARB and CCB is very effective in lowering BP and UAE in cases in which BP is not well controlled, while, even in patients with a sufficient BP control of <130/85 mmHg, the use of ARB singly resulted in a significant decrease in UAE without a further decrease in BP, implying that the ARB had a renoprotective action independent of changes in BP.

The p53 tumor suppressor gene may act as an inhibitor of vascular neointima formation in response to injury and in the present study the effects of p53 deficiency on external vascular cuff-induced neointima formation were evaluated. Vascular neointima formation was induced by an external vascular cuff; a polyethylene tube placed around a 2 mm segment of the left femoral artery ensheathed the adventitia, but avoided direct intraluminal injury. Two weeks after cuff placement, the cuff-sheathed and contralateral control arteries without cuff from wild-type (n=10) and p53 deficient (n=8) mice were harvested and analyzed by quantitative morphometry. The areas of the lumen, intima, and media were measured in 10 cross-sections from one edge to the other of the cuffed portion, and in the corresponding 2-mm segment of the contralateral control artery. The volume ratio of the intima to media (I/M) was calculated. The contralateral control arteries without a cuff did not have intima in either wild-type or p53 deficient mice. In the cuff-sheathed arteries, neointima formation of p53 deficient mice with an I/M of 93% was significantly greater than that of wild-type mice with an I/M of 50% (P=0.001). The absence of p53 is associated with increased neointima formation in response to cuff injury.

An increase in the serum creatine kinase (CK) level is one of the side effects of theophylline; on rare occasions, the increase may be followed by rhabdomyolysis. Theophylline is often administered with drugs that potentially elevate the serum CK level (CK-elevating drugs) such as beta-agonists and steroids. However, the effects of the combined treatment of theophylline and CK-elevating drugs have not been reported. We, therefore, retrospectively investigated the effects of combined treatment on the serum CK level, in 391 asthmatic outpatients. In this study, the number and type of the CK-elevating drugs administered, and the serum levels of CK and theophylline, were investigated. The patients were divided into four groups: the theophylline-treated and CK-elevating drug-treated group, the theophylline-treated and non-CK-elevating drug-treated group, the non-theophylline-treated and CK-elevating drug-treated group, and the non-theophylline-treated and non-CK-elevating drug-treated group. The theophylline-treated and CK-elevating drug-treated group showed about 100% higher serum CK levels (225 IU/L) than any other group (102-124 IU/L), and no increase in the serum theophylline level. This result indicates that there is a synergistic effect of theophylline and CK-elevating drugs on the serum CK level. The combined treatment of theophylline and CK-elevating drugs induces a synergistic increase in the serum CK level, indicating not pharmacokinetic but pharmacodynamic interactions with these drugs.